CN113795506A - 用于治疗CD1a阳性癌症的CAR T细胞 - Google Patents
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Abstract
复发性/难治性T细胞急性淋巴母细胞白血病(T‑ALL)具有令人沮丧的结局,并且没有针对T‑ALL的有效的靶向免疫疗法。嵌合抗原受体T细胞(CART)向T‑ALL的拓展仍然具有挑战性,因为CART和T‑ALL原始细胞之间靶抗原的共同表达导致CART相残。CD1a仅在T‑ALL的一个主要亚类皮质T‑ALL中表达。CD1a的表达仅限于皮质胸腺细胞,CD34+祖细胞和T细胞在个体发育过程中都不表达CD1a,从而限制了靶向/非肿瘤毒性的风险。本发明提供包含可被转导或转化到T细胞中的CD1a靶向部分的CAR。由此产生的CART适用于皮质T‑ALL的治疗。
Description
技术领域
本发明提供用于治疗CD1a阳性癌症例如T细胞急性淋巴母细胞白血病和T细胞淋巴母细胞性淋巴瘤的疗法。特别地,本发明提供了可以靶向CD1a的嵌合抗原受体(Chimericantigen receptor,CAR)T细胞。
背景技术
T细胞系急性淋巴母细胞白血病(T-cell lineage acute lymphoblasticleukemia,T-ALL)是一种由胸腺T细胞前体的白血病性转化引起的恶性疾病1。T-ALL具有表型和遗传异质性,并且通常与涉及造血干/祖细胞(Hematopoietic stem/progenitorcell,HSPC)稳态和T细胞发育的主要调节因子的转录因子的遗传改变/突变相关2。T-ALL在儿童和成人中诊断出的所有急性白血病中分别占10%至15%和20%至25%3,4,中位诊断年龄为9岁5-7。强化化疗方案提高了T-ALL患者的生存率。然而,无事件生存率(Event-freesurvival,EFS)和总生存率(Overall survival,OS)仍然<70%,并且复发性/难治性(Relapsed/refractory,R/R)T-ALL的结局特别差。除了造血细胞移植和常规化疗之外,目前没有潜在的治疗选择,这与对毒性的巨大权衡相关4,8,从而强化了对新型靶向治疗的需求。T细胞淋巴母细胞性淋巴瘤(T-cell lymphoblastic lymphoma,TCL)在病因和致病性上与T-ALL不同,但在表型上非常相似。主要区别在于TCL存在于髓外,而T-ALL是一种骨髓疾病。
免疫疗法在癌症治疗中产生了前所未有的期望,并依赖作为对抗癌症的有力武器的免疫系统。近年来,基于嵌合抗原受体(Chimeric antigen receptor,CAR)的过继细胞免疫治疗显示出巨大的潜力。CAR疗法将转基因T细胞重新定向,以独立于主要组织相容性复合物的方式特异性识别和消除表达特定抗原的肿瘤细胞9,10。现在CAR T细胞(CAR T-cell,CART) 重新定向于CD19或CD22的成功对于B细胞恶性肿瘤(主要是B-ALL)来说是无可争议的11-14。但是,由于CART和T系肿瘤细胞之间靶抗原的共同表达,使用CART靶向T细胞恶性肿瘤的策略仍然具有挑战性。在这方面,针对泛T细胞抗原的CART具有两个主要缺点: i)CART自我靶向/相残(fratricide),和ii)T细胞发育不全,导致危及生命的免疫缺陷15-17。
最近的研究表明,用表达最多的泛T细胞抗原CD7、CD3、CD5或TCR CAR转导的T 细胞在体外有效消除T-ALL原始细胞(blast),并能够在体内控制疾病15-20。然而,在CAR 转导之前,还需要使用诸如CRISPR/Cas9基因组编辑或蛋白质表达阻断剂等离临床还很远的方法来破坏T细胞中的靶抗原,以避免广泛的自身抗原驱动的相残15-17,19。
因此,仍然需要能够成功治疗T-ALL的疗法。本发明旨在提供一种治疗CD1a阳性T-ALL的疗法。
附图说明
图1.T-ALL和正常造血作用和胸腺生成中的CD1a表达。(A)指定标志物的从头(denovo)T-ALL样本(n=38)的免疫表型。上部的大括号和中间的大括号分别标识CD1a+/++和CD1a低/+/+coT-ALL患者。底部的黑色圆圈示出了非coTALL患者。(B)coT-ALL患者的代表性FACS点图。CD7+CD1a+细胞是coT-ALL原始细胞,CD3+CD7+CD1a-(CD4+或CD8+) 是诊断样本中存在的正常成熟T细胞。(C)CD1a在复发时保持(n=5对诊断复发coT-ALL)。数据显示为复发样本中相对于诊断匹配样本的CD1a表达(诊断示出为100%表达)。(D)T 细胞和CD34+HSPC在个体发育过程中不表达CD1a。(E)描述发展中的胸腺T细胞群的表型的方案。(F)前皮层(CD34高CD7++CD1a-)胸腺细胞和皮层(CD34+CD7++CD1a+)胸腺细胞的代表性FACS。DX:诊断。RX:复发。
图2.CD1a CART在体外特异性靶向并消除CD1a+T-ALL细胞系。(A)所使用的CD1aCAR构建体的方案。(B)使用抗scFv MoAb和GFP在293T细胞中检测CAR。(C)CD4+T 细胞和CD8+T细胞中的代表性CAR转导和检测(n=6)。(D)适当的T细胞活化(n=3)。 (E)用空白(Mock)或CD1a CAR转导的活化T细胞的稳健扩增显示没有相残的迹象(n=4)。 (F)在Jurkat、MOLT4和NALM6细胞系中的CD1a(黑线)的表面表达。(G)细胞系、原发性coT-ALL样品和原发性移植物(primograft)中的CD1a抗原密度。(H)在16小时测定中以指定的E:T比率进行测定的CD1a CART和MOCK T细胞对coT-ALL和B-ALL细胞系的细胞毒性(n=4)。(I)在1:1的E:T比率下,在72小时细胞毒性测定中通过FACS测量的活eFluor+靶细胞的绝对计数。(J)对用eFluor670标记的靶细胞进行的细胞毒性的代表性FACS 分析。(K)ELISA示出了在16小时测定中1:1的E:T比率下,暴露于Jurkat和NALM6(阴性对照)细胞的CD1a CART产生了高水平的炎性细胞因子IL-2、TNFα和IFNγ(n=4)。*p< 0.05,**p<0.01,***p<0.001。
图3.CD1a CART特异性靶向并消除来自原发性样本或PDX模型的体外CD1a+T-ALL原始细胞。(A)CD1a对比CD7在来自原发性患者/原发性移植物的coT-ALL原始细胞中的表达。示出了CD1a+原始细胞的百分比。(B)在4:1的E:T比率下,通过FACS在48小时细胞毒性测定中测量的细胞毒性(以eFluor+细胞的绝对计数计)(n=3)。(C)在细胞毒性测定结束时对eFluor标记的靶细胞内的CD1a进行代表性FACS分析,揭示了CD1a CART的特异性(n=3)。(D)在4:1的E:T比率下,在16小时测定中通过ELISA(n=3份独立上清液) 分析出CD1a CART产生了高水平的促炎细胞因子。*p<0.05,**p<0.01,***p<0.001,****p <0.0001。
图4.CD1a CART在小鼠异种移植环境中完全控制coT-ALL细胞的进展。(A)异种移植模型的方案。NSG小鼠(n=6只/组)静脉内(i.v.)注射3×106个表达Luc-GFP的Jurkat细胞,然后3天后进行单次静脉内注射5×106个空白或CD1a CART。使用IVIS成像通过生物发光(Bioluminescence,BLI)每4-6天监测一次肿瘤负荷。当MOCK治疗的动物完全是白血病时,将一半的CD1a CART治疗的动物处死并通过FACS(BM、PB和脾脏)分析白血病负荷和CART的持续性。其余的动物在6周后用1.5×106个Luc-Jurkat再次攻击,并像以前一样进行跟踪。(B)在指定时间点通过BLI监测的肿瘤负荷的IVIS成像。(C)指定时间点的总辐射定量(p/sec/cm2/sr)。处死。(D)在CART输注17天后,PB中的循环Jurkat细胞。 (E)第17天PB中的T细胞持续性,以及处死时的脾脏和BM。数据显示为平均值±SD(n=6 只小鼠/组)。*p<0.05,**p<0.01,***p<0.001。
图5.CD1a CART完全消除了PDX环境中原发性CD1a+coT-ALL细胞的进展。(A)PDX模型的方案。NSG小鼠(n=5-6只/组)静脉内注射1×106个原发性coT-ALL细胞,然后3天后进行单次静脉内注射1×106个空白或CD1a CART。在6周和9周后的出血并BM抽吸之前,每隔一周通过FACS监测肿瘤负荷。(B、C)注入CART后6周和9周,BM(B)和PB (C)中白血病小鼠的频率和白血病水平。左图示出了代表性的FACS统计图。原发性CD1a+T- ALL原始细胞显示在框内(灰色)。效应T细胞以灰色显示在框外。小鼠细胞以黑色显示。 (D)接受CD1a CART或MOCK T细胞的coT-ALL原发性移植物的9周的OS。(E)PB(第 2周到第9周)和BM(第6周和第9周)中效应T细胞的持续时间。每个点代表一个独立的小鼠。**p<0.01,马尔科姆-考克斯(Malcolm-Cox)检验。
图6.CD1a CART在再次攻击PDX环境中保留了控制CD1a+细胞系和coT-ALL原发性样本进展的能力。(A)再次攻击的小鼠中Jurkat细胞负荷的IVIS成像。(B)在用Jurkat细胞再次攻击的小鼠中随时间的总辐射定量(p/sec/cm2/sr)。(C)再次攻击16天后,PB中的循环Jurkat细胞。(D)在再次攻击的动物被处死时,PB、BM和脾脏中强健的效应T细胞的持续性。(E)使用coT-ALL原发性样品再次攻击PDX实验的方案。在初始CART输注七周后,再次用1×106个原发性CD1a+T-ALL的攻击携带CART的PDX小鼠。(F)白血病再次攻击 6周后移植的PB(左图)和BM(右图)中的二次coT-ALL负荷。(G)来自用coT-ALL原发性样本再次攻击的PDX的PB中效应T细胞随时间的持续性(第2周、第4周和第6周)。每个点代表一个独立的小鼠。*p<0.05,**p<0.01,***p<0.001,****p<0.0001。
图7.呈现的来自coT-ALL患者的CD1a CART特异性裂解自体CD1a+T-ALL原始细胞。(A)描述自体细胞毒性试验的实验设计的方案。从coT-ALL患者的PB中用FACS纯化成熟 (正常)CD3+CD1a-T细胞,用CD1a CAR进行感染,扩增,并暴露于自体总PBMC。(B) 以1:1和4:1的E:T对自体细胞毒性进行48小时测定的FACS分析。eFluor670标记的总 PBMC靶群体包含CD1a+T-ALL原始细胞(上框)和成熟CD3+CD1a-T细胞(下框)。(C) CD1a CART介导的对coT-ALL原始细胞(上图)和CD3+CD1a-成熟T细胞(下图)的特异性裂解的量化。(D)ELISpot示出了来自空白的对比用来自CMV、EBV和Flu(CEF)的肽池刺激的CD1a CART的IFNγSFC的数量。葡萄球菌肠毒素B(Staphylococcal enterotoxin B, SEB)用作阳性对照。
图8.本研究中出现的每个CD1a++coT-ALL患者的免疫表型。(A)区分成熟正常T细胞 (CD3++CD1a-(CD4+或CD8+))和coT-ALL原始细胞(CD7+CD1a+)的门控策略。请注意,coT-ALL原始细胞通常具有CD3和/或CD4/CD8的异常表达。(B)可用的CD1a++coT- ALL患者(n=16)的CD7/CD3对比CD1aFACS点图,示出了成熟正常T细胞(左象限)和 coT-ALL原始细胞(右象限)的百分比。
图9.CD1a CART的体外特异性。(A)本研究中使用的CD1aCAR、CD22CAR和MOCK 构建体的方案。(B)CD1a CART而不是CD22 CART裂解T-ALL细胞系Jurkat。CD22 CART 而不是CD1a CART裂解B-ALL系NALM6。*p<0.05,**p<0.01,***p<0.001,****p< 0.0001。
图10.CD1a CART的体内细胞毒性是剂量依赖性的。(A)在实验开始时通过BLI监测的肿瘤负荷(尺度:3×104p/sec/cm2/sr至1×105p/sec/cm2/sr),确认了早期和有效的T-ALL植入。 (B)CART剂量为2×106p/sec/cm2/sr和5×106p/sec/cm2/sr时在指定时间点通过BLI监测的肿瘤负荷的IVIS成像。(C)CART剂量为2×106和5×106时在指定时间点的总辐射定量 (p/sec/cm2/sr)。N=3-4只小鼠/组。处死。*p<0.05,**p<0.01,***p<0.001,****p< 0.0001。
图11.CD1a CART不靶向于CD7+CD1a-胸腺细胞。在4:1的E:T下,在16小时和72小时进行的CD1a CART和空白T细胞的针对胎儿胸腺细胞的细胞毒性测定(n=2)。
图12.CD1a-原发性coT-ALL细胞的绝对数量在MOCK或CD1a CART暴露后保持相同。这证实了CD1a表达不会因免疫压力而损失/下调。
发明内容
对我们希望重定向T细胞所针对的抗原的选择代表了解决与正常和恶性T细胞之间T细胞标志物的共同表达相关的问题的重大进步。我们证明了脂质呈递分子CD1a是治疗T-ALL 一大亚类(即皮质T-ALL)的合适靶点。
我们开发并在功能上表征了CD1a特异性CART,其在异种移植模型中在体外和体内均对T-ALL细胞系和原发性皮质CD1a+T-ALL细胞显示出强大的细胞毒性。CD1a CART持续扩增200倍,类似于空白T细胞,从而验证了将CART重定向到CD1a抗原不会诱导T细胞相残。此外,将CD1a CART用于皮质T-ALL绕过了作为避免自身抗原驱动的相残的策略的在CAR转导之前对T细胞中靶抗原进行复杂的基于基因组编辑的破坏的需要15-17,19。我们进一步证明,在稳态造血中,CD1a仅在皮质CD34+CD7+胸腺T祖细胞的一个亚类中表达,而早期的CD34高CD7高T祖细胞缺乏CD1a。此外,在个体发育过程中,来自多种组织的正常 CD34+HSPC和成熟T细胞都不表达CD1a,从而最大限度地降低了中靶/脱瘤(on-target/off- tumor)的毒性的风险。事实上,当人类胎儿胸腺衍生的CD7+胸腺细胞暴露于CD1a CART时,只有CD1a+皮质胸腺细胞被CD1a CART消除,而发育较早和较晚的胸腺T系群体(CD34+ 和CD34-)不被靶向,这将中靶/脱瘤效应限制在皮质胸腺细胞的发育瞬态胸腺群,并进一步证实了CD1a CART的抗相残性。
皮质胸腺细胞独特的胸腺定位,以及在生理上/不断成熟为功能性T细胞的 CD34+CD7+CD1a-T细胞祖细胞的胸腺亚群位于CD1a+皮质胸腺细胞的上游这一事实,为在 R/R T-ALL患者中使用CD1a CART提供了额外的安全水平。我们预计CD1a CART不会导致不可逆的毒性或严重的T细胞发育不全,原因如下:i)CD1a+胸腺细胞群是短暂的胸腺T细胞部分,最终由上游CD1a-T细胞祖细胞再生;ii)CD1a CART本身对病毒抗原有正常反应,因此可能针对病原体具有保护性;iii)针对CD5或CD7的特异性抗体的临床使用42没有显示出严重或不可逆的毒性;iv)有多项研究验证了T细胞的胸腺外成熟以及先天免疫系统和适应性免疫系统之间的平衡,这至少可以部分保证了经历过部分或全部胸腺切除术的患者的免疫保护45-47。
因此,一方面,本发明提供了一种嵌合抗原受体(CAR),其包含含有CD1a靶向部分的胞外结构域、跨膜结构域和胞内信号传导结构域。
本发明还提供了编码本发明的CAR的核酸。此外,本发明提供了包含本发明的核酸和/ 或CAR的细胞。并且,本发明提供了包含多个根据本发明的细胞和药学上可接受的载体或稀释剂的药物组合物。
提供了本发明的细胞或本发明的药物组合物用作药物。特别地,本发明提供了一种治疗 CD1a阳性癌症的方法,该方法包括向有需要的患者施用本发明的细胞或本发明的药物组合物。
具体实施方式
定义
“给予”或“施用”药物给患者(以及该短语的语法等价物)是指直接施用,这可以是由医学专业人员对患者施用或可以是自我施用,和/或可能是开药行为的间接施用。例如,指导患者自行施用或为患者提供药物处方的医生正在向患者施用药物。
术语“亲和体”是指源自蛋白质A的Z结构域并经工程改造以与特定靶标结合的蛋白质 (参见Frejd&Kim,2017.Exp Mol Med.49(3):e306)。
术语“抗体”是指包含至少一个与特定靶标结合或与特定靶标发生免疫反应的免疫球蛋白结构域的分子。该术语包括完整抗体和任何抗原结合部分或其单链及其组合;例如,术语“抗体”特别包括二价抗体和二价双特异性抗体。
典型类型的抗体包含通过二硫键相互连接的至少两条重链(Heavy chain,HC)和两条轻链(Light chain,LC)。
每个“重链”包含“重链可变结构域”(本文缩写为“VH”)和“重链恒定结构域”(本文缩写为“CH”)。重链恒定结构域通常包含三个恒定结构域:CH1、CH2和CH3。
每条“轻链”包含“轻链可变结构域”(本文缩写为“VL”)和“轻链恒定结构域”(“CL”)。轻链恒定结构域(CL)可以是κ型或λ型。VH结构域和VL结构域可以进一步细分为高度可变区,称为互补决定区(Complementarity Determining Region,CDR),其间夹杂着较为保守的区,称为框架区(Framework region,FW)。
每个VH和VL由三个CDR和四个FW组成,从氨基端到羧基端按以下顺序排列:FW1、CDR1、FW2、CDR2、FW3、CDR3、FW4。本公开尤其提供了VH序列和VL序列以及对应于CDR1、CDR2和CDR3的子序列。
可以使用许多众所周知的方案中的任何一种来确定给定CDR的精确氨基酸序列边界,包括Kabat et al.(1991),“Sequences of Proteins of Immunological Interest,”5th Ed.Public Health Service,National Institutes of Health,Bethesda,MD(编号方案“Kabat”)、Al-Lazikani et al.,(1997) JMB 273,927-948(编号方案“Chothia”)中描述的那些。
因此,本领域技术人员将理解,FW1、FW2、FW3和FW4的序列同样公开。对于特定的VH,FW1是VH的N端和H-CDR1的N端之间的子序列,FW2是H-CDR1的C端和H- CDR2的N端之间的子序列,FW3是H-CDR2的C端和H-CDR3的N端之间的子序列,FW4 是H-CDR3的C端和VH的C端之间的子序列。类似地,对于特定的VL,FW1是VL的N 端和L-CDR1的N端之间的子序列,FW2是L-CDR1的C端和L-CDR2的N端之间的子序列。FW3是L-CDR2的C端和L-CDR3的N端之间的子序列,FW4是L-CDR3的C端和VL 的C端之间的子序列。
重链和轻链的可变结构域包含与结合靶标相互作用的区域,并且与结合靶标相互作用的该区域在本文中也称为“抗原-结合位点”或“抗原结合位点”。抗体的恒定结构域可以介导抗体与宿主组织或因子的结合,该宿主组织或因子包括免疫系统的各种细胞(例如,效应细胞) 和经典补体系统的第一组分(C1q)。本公开的示例性抗体包括典型的抗体,但也包括二价片段和其变体,例如F(ab’)2。
如本文所用,术语“抗体”包括完整的多克隆抗体、完整的单克隆抗体、二价抗体片段(例如F(ab')2)、多特异性抗体(例如双特异性抗体)、嵌合抗体、人源化抗体、人抗体和任何包含抗原结合位点的其他修饰的免疫球蛋白分子。
抗体可以具有免疫球蛋白的任何五个主要类别(同种型):IgA、IgD、IgE、IgG和IgM,或其亚类(例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2),分别基于它们的被称为α、δ、ε、γ和μ的重链恒定结构域。不同类别的免疫球蛋白具有不同的且已知的亚基结构和三维构型。抗体可以是裸抗体或与其他分子如治疗剂或诊断剂缀合以形成免疫缀合物。
术语“anticalin”是指衍生自脂质运载蛋白并经工程改造以结合特定靶标的蛋白质(参见 Skerra,2008.FEBS J.275(11):2677-83)。
术语“抗原结合片段”或“Fab”是指包含重链和轻链的各自的一个恒定结构域和一个可变结构域的抗体片段。Fab片段可以通过用木瓜蛋白酶消化完整的单克隆抗体来获得。
术语“癌症”是指一组疾病,其可定义为任何异常的良性或恶性新生长,这种异常的良性或恶性新生长不具有生理功能的组织的,由不受控制的通常快速的细胞增殖引起,并有可能侵入或扩散到身体的其他部位。
术语“CD1a”是指非多态性MHC1类相关细胞表面糖蛋白,与β-2-微球蛋白相关地表达。 CD1a由皮质胸腺细胞、朗格汉斯(Langerhans)细胞和交错突细胞表达。CD1a也在T细胞系的一些恶性肿瘤和朗格汉斯细胞组织细胞增生症中表达。CD1a在皮质胸腺细胞、表皮朗格汉斯细胞、树突细胞、某些T细胞白血病和各种其他组织中表达。CD1a在结构上与主要组织相容性复合物(MHC)蛋白相关,并与β-2-微球蛋白形成异二聚体。与人CD1a相关的示例性序列和数据已以ID号P06126保存在UniProtKB数据库中。
“CD1a阳性”癌症,包括“CD1a阳性”癌性疾病,是一种包含其细胞表面存在CD1a的细胞的癌症。术语“CD1a阳性”还指在其细胞表面产生足够水平的CD1a的癌症,这使得本发明的含CAR的细胞能够具有通过CAR与CD1a结合而介导的治疗效果。在一些实施方式中,CD1a阳性癌症是皮质T细胞急性淋巴母细胞白血病和T细胞淋巴母细胞性淋巴瘤或朗格汉斯细胞组织细胞增生症(Langerhans cell histiocytosis,LCH)。
术语“CD1a靶向部分”是指能够结合CD1a的物质。在关于CAR的上下文中,CD1a靶向部分使T细胞靶向CD1a阳性细胞,优选癌细胞。在关于CAR的上下文中,应理解CD1a靶向部分是可遗传编码的。
术语“嵌合抗原受体”或“CAR”是指使T细胞靶向选定的抗原并重新编程T细胞功能、代谢和持续性的合成受体(参见Rivière&Sadelain,2017.Mol Ther.25(5):1117-1124)。类似地,术语“CART”是指包含CAR的T细胞。
如本文所用,“组合疗法”、“与……组合”或“与……结合”表示使用至少两种不同的治疗方式(即化合物、组分、靶向剂或治疗剂)的任何形式的并行、平行、同时、顺序或间歇治疗。因此,该术语是指在向对象施用一种治疗方式之前、期间或之后施用另一种治疗方式。组合的方式可以任何顺序施用。治疗活性方式以由医疗护理人员或根据监管机构规定的方式和给药方案一起(例如,同时在同一或单独的组合物、制剂或单位剂型中)或单独(例如,在同一天或在不同天,并且根据单独的组合物、制剂或单位剂型的适当给药方案以任何顺序)施用。一般而言,每种治疗方式将以针对该治疗方式确定的剂量和/或时间表来施用。可选地,可以在组合疗法中使用三种或更多种方式。此外,本文提供的组合疗法可以与其他类型的治疗结合使用。例如,其他抗癌治疗可以选自由化学疗法、外科手术、放射疗法(放射)和/或激素疗法,以及与对象的当前护理标准相关的其他治疗组成的组。
“完全响应(Complete response)”或“完全缓解(Complete remission)”或“CR”表示所有靶病灶消失,如RECIST v1.1指南中所定义。这并不总是意味着癌症已经治愈。
术语“共刺激信号传导结构域”是指向T细胞提供信号的信号传导部分,其除了由例如 TCR/CD3复合物的CD3ζ链提供的主要信号外,还介导T细胞应答,包括但不限于活化、增殖、分化、细胞因子分泌等。共刺激结构域可以包括但不限于CD27、CD28、4-1BB(CD137)、OX40(CD134)、CD30、CD40、1COS、淋巴细胞功能相关抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C、B7-H3以及与CD83特异性结合的配体的全部或部分。在一些实施方式中,共刺激信号传导结构域是与其他细胞内介质相互作用以介导细胞反应(包括活化、增殖、分化和细胞因子分泌等)的胞内信号传导结构域。
术语“设计的锚蛋白重复序列蛋白(Designed ankyrin repeat protein)”或“DARPin”是指源自已经工程改造为与特定靶标结合的锚蛋白重复序列的蛋白质(参见Plückthun,2015.Annu Rev Pharmacol Toxicol.55:489-511)。
“无病生存期(Disease free survival,DFS)”是指治疗期间和治疗后患者保持无病状态的时间长度。
如本文所用,制剂,例如治疗剂,比如CART,其术语“有效量”是足以实现有益或期望结果例如临床结果的量,并且因此“有效量”取决于其应用的上下文。例如,在施用治疗T-ALL 的治疗剂的上下文中,有效量可以:减少癌细胞的数量;减少肿瘤大小或负荷;抑制(即,在一定程度上减缓,以及在某个实施方式中停止)癌细胞浸润到外周器官中;抑制(即,在一定程度上减缓,以及在某个实施方式中停止)肿瘤转移;在一定程度上抑制肿瘤生长;在一定程度上缓解与癌症相关的一种或多种症状;和/或导致有利的反应,例如,无进展生存期 (progression-free survival,PFS)、无病生存期(DFS)或总生存期(OS)、完全响应(CR)、部分响应(Partial response,PR)增加,或在某些情况下,稳定疾病(Stabledisease,SD)、进展性疾病(Progressive disease,PD)减少、进展时间(Time toprogression,TTP)缩短或其任何组合。术语“有效量”可与“有效剂量”、“治疗有效量”或“治疗有效剂量”互换使用。
术语“fynomer”是指源自人Fyn激酶的SH3结构域且已被工程改造为与特定靶标结合的的蛋白质(参见Bertschinger et al.,2007.Protein Eng Des Sel.20(2):57-68)。
术语“个体”、“患者”或“对象”在本申请中可互换使用,其指定为人类且无意以任何方式进行限制。“个体”、“患者”或“对象”可以具有任何年龄、性别和身体状况。术语“有需要的患者”通常是指患有CD1a阳性癌症的患者。
“输注(infusion/infusing)是指为了治疗目的通过静脉将含有治疗剂的溶液引入体内。通常,这是通过静脉输液袋实现的。
如本文所用,“胞内信号传导结构域”是指提供淋巴细胞活化的分子(此处为嵌合受体分子)的一个或多个结构域的全部或一部分。此类分子的胞内结构域通过与细胞介质相互作用来介导信号,从而导致增殖、分化、活化和其他效应子功能。用于本发明CAR的胞内信号传导结构域的实例包括CD3ζ链的胞内序列和/或协同作用以在CAR接合后启动信号转导的共受体,以及这些序列和任何具有相同功能的合成序列的的任何衍生物或变体。T细胞活化可以说是由两类不同的细胞质信号传导序列介导的:启动依赖抗原的初级活化并提供T细胞受体样信号的细胞质信号传导序列(初级细胞质信号传导序列)和以抗原非依赖性方式作用以提供次级或共刺激信号的细胞质信号传导序列(次级细胞质信号传导序列)。以刺激方式作用的初级细胞质信号传导序列可能包含信号传导基序,这些信号传导基序被称为基于受体酪氨酸的活化基序或ITAM。含有初级细胞质信号传导序列的ITAM的例子包括那些源自CD3ζ、 FcRγ、CD3γ、CD3δ、CD3ε、CD5、CD22、CD79a、CD79b和CD66d的序列。
术语“单体”是指源自III型纤连蛋白结构域且已被工程改造为与特定靶标结合的蛋白质 (参见Koide et al.,2013.J Mol Biol.415(2):393-405)。
术语“纳米抗体”是指包含重链抗体、优选骆驼重链抗体的可溶性单一抗原结合V结构域的蛋白质(参见Bannas et al.,2017.Front Immunol.8:1603)。
“总生存期”(OS)是指从患者入组到死亡或在最后已知存活的日期进行检查的时间。OS 包括与初发或未治疗的个体或患者相比,预期寿命的延长。总生存期是指患者例如从诊断或治疗之时起保持存活所确定的时间段(例如一年、五年等)的情况。
“部分响应”或“PR”是指响应于治疗,以基线总直径为参考,靶病灶直径总和减少至少30%,如RECIST v1.1指南中所定义。
术语“肽适体”是指可与特定靶标结合的5个至20个氨基酸残基的短序列。肽适体通常插入稳定蛋白质支架的环区域内(参见Reverdatto et al.,2015.Curr Top MedChem.15(12):1082- 101)。
如本文所用,“药学上可接受的载体”或“药学上可接受的稀释剂”意指与药物施用相容的任何和所有的溶剂、分散介质、包衣、抗菌剂和抗真菌剂、等渗剂和吸收延迟剂。这种介质和试剂用于药物活性物质的用途是本领域众所周知的。可接受的载体、赋形剂或稳定剂在所采用的剂量和浓度下对接受者是无毒的,并且在不限制本发明范围的情况下,包括:额外的缓冲剂;防腐剂;共溶剂;抗氧化剂,包括抗坏血酸和甲硫氨酸;螯合剂,例如EDTA;金属络合物(例如,Zn-蛋白络合物);可生物降解的聚合物,例如聚酯;成盐抗衡离子,例如钠、多元糖醇;氨基酸,例如丙氨酸、甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸、赖氨酸、鸟氨酸、亮氨酸、2-苯丙氨酸、谷氨酸和苏氨酸;有机糖或糖醇,例如乳糖醇、水苏糖、甘露糖、山梨糖、木糖、核糖、核糖醇、肌肉肌糖(myoinisitose)、肌醇、半乳糖、半乳糖醇、甘油、环醇(例如,纤维醇)、聚乙二醇;含硫还原剂,例如尿素、谷胱甘肽、硫辛酸、硫代乙醇酸钠、硫代甘油、α-单硫代甘油和硫代硫酸钠;低分子量蛋白质,例如人血清白蛋白、牛血清白蛋白、明胶或其他免疫球蛋白;以及亲水性聚合物,例如聚乙烯吡咯烷酮。其他药学上可接受的载体、赋形剂或稳定剂,例如在1980年Osol,A.主编的第16版雷明顿药物科学(Pharmaceutical Sciences 16th edition,Osol,A.Ed.(1980))中描述的那些也可以包括在本文所述的药物组合物中,前提是它们不对药物组合物的所需特性产生不利影响。
“进展性疾病”或“已经进展的疾病”是指又一个新的病灶或肿瘤的出现和/或现有非靶病灶的明确进展,如RECIST v1.1指南中所定义。进展性疾病或已经进展的疾病也可以指自治疗开始以来肿瘤由于肿瘤的质量增加或扩散而生长超过20%。
“无进展生存期”(PFS)是指从入组到疾病进展或死亡的时间。PFS通常使用Kaplan-Meier 方法和实体瘤反应评估标准(Response Evaluation Criteria in SolidTumors)(RECIST)1.1标准来测量。一般来说,无进展生存是指患者仍然活着,而癌症没有恶化的情况。
术语“RECIST”是指实体瘤反应评估标准。RECIST指南、准则或标准描述了实体瘤测量的标准方法和用于成人和儿童癌症临床试验的客观评估肿瘤大小变化的定义。RECISTv1.1是指修订后的RECIST指南的1.1版本,它发表在European Journal of Cancers 45(2009)228-247 上。
术语“repebody”是指源自富含亮氨酸的重复模块并经工程改造以与特定靶标结合的蛋白质(参见Lee et al.,2012.PNAS.109(9):3299-3304)。
术语“积极响应”通常是指在对象中引起有益状态。关于癌症治疗,该术语是指向对象提供治疗效果。可以通过多种方式测量癌症的积极治疗效果(参见Weber,2009.J NuclMed.50 Suppl 1:1S-10S)。例如,肿瘤生长抑制、分子标志物表达、血清标志物表达和分子成像技术均可用于评估抗癌疗法的疗效。关于肿瘤生长抑制,根据NCI标准,T/C≤42%是抗肿瘤活性的最低水平。T/C<10%被认为是高抗肿瘤活性水平,其中T/C(%)=治疗的中值肿瘤体积/对照的中值肿瘤体积×100。例如,可以通过无进展生存期(PFS)、无病生存期(DFS)、或总生存期(OS)、完全响应(CR)、部分响应(PR)增加,或在某些情况下,稳定疾病(SD)、进展性疾病(PD)减少、进展时间(TTP)缩短或其任何组合来评估积极响应。
术语“序列同一性”是指当使用成对序列比对工具来比较两个序列时获得的百分比值。在本案例中,使用全局比对工具“EMBOSS Needle”使用默认设置获得序列同一性(Rice et al., 2000.Trends Genet.16(6):276-7;Li et al.,2015.Nucleic AcidsRes.43(W1):W580-4)。全局比对工具获得自:https://www.ebi.ac.uk/Tools/psa/。
术语“单链抗原结合片段”或“scFab”是指一种融合蛋白,该融合蛋白包含抗体的轻链的一个可变结构域和一个恒定结构域,其与抗体的重链的一个可变结构域和一个恒定结构域连接,其中重链和轻链通过短肽连接在一起。
术语“单链可变片段”或“scFv”是指包含抗体的重链和轻链的可变结构域的融合蛋白,该可变结构域通过肽接头彼此连接。该术语还包括二硫化物稳定的Fv(dsFv)。用二硫键稳定 scFv的方法在Reiter et al.,1996.Nat Biotechnol.14(10):1239-45中公开。
“稳定疾病”是指没有进展或复发的疾病,如RECIST v1.1指南中所定义。在稳定疾病中,既没有足够的肿瘤缩小来满足部分响应的条件,也没有足够的肿瘤增加来满足进展性疾病的条件。
“肿瘤进展时间”(Time to Tumor Progression,TTP)定义为从入组到疾病进展的时间。通常使用RECIST v1.1标准对TTP进行测量。
如本申请中所使用的,术语“治疗”和“疗法”是指以修复健康问题为目标意在用于治愈和/ 或减轻疾病和/或症状的一组卫生的、药理的、外科的和/或物理的手段。术语“治疗”和“疗法”包括预防性方法和治愈性方法,因为两种方法均针对个体或动物的健康的维持和/或重建。不论症状、疾病和失能的起源如何,在本申请的上下文中,应把施用合适的药物以减轻和/或治疗健康问题解释为治疗或疗法的一种形式。
嵌合抗原受体
一方面,本发明提供了一种嵌合抗原受体(CAR),其包含含有CD1a靶向部分的胞外结构域、跨膜结构域和胞内信号传导结构域。
CD1a靶向部分
在一些实施方式中,CD1a靶向部分是与CD1a特异性结合的抗体、anticalin、repebody、单体、scFv、Fab、scFab、亲和体、fynomer、DARPin、纳米抗体或肽适体。
与CD1a特异性结合的结合分子可能对诊断和治疗上述疾病非常有用。本领域已知几种针对CD1a的鼠单克隆抗体(Kelly(1994),Amiot et al.(1986),Furue et al.(1992))。然而,由于与向人施用鼠抗体相关的问题,例如短的血清半衰期、无法触发某些人效应子功能以及针对鼠抗体的不希望的免疫反应的产生,鼠抗体在体内使用受到限制(VanKroonenburgh and Pauwels(1988))。近年来,开发了新型人抗体(Bechan(2012),andGitanjali(2005)),克服了前面提到的这些缺点。除了NA1/34.HLK之外,其他杂交瘤可从SIGMA ALDRICH商购,例如是OKT6(IgG1同种型)。
请参阅:
·Amiot M.,Bernard A.,Raynal B.,Knapp W.,Deschildre C.and Boumsell L.(1986),J. Immunol.136:1752-1757.
·Furue M.,Nindl M.,Kawabe K.,Nakamura K.,Ishibashi Y.and Sagawa K.(1992),J.Am. Acad.Dermatol.27:419-42
·Kelly K.M.,Beverly P.C.,Chu A.C.,Davenport V.,Gordon I.,Smith M.andPritchard J. (1994),J.Pediatr.125:717-722
·Van Kroonenburgh M.J.and Pauwels E.K.(1988),Nucl.Med.Commun.9:919-930.
·Gitanjali Bechan,David W.Lee,R.Maarten Egeler and Robert J.ArceciBlood 2005 106:4815
Bechan,G.I.,Lee,D.W.,Zajonc,D.M.,Heckel,D.,Xian,R.,Throsby,M.,Meijer,M., Germeraad,W.T.,Kruisbeek,A.M.,Maarten Egeler,R.and Arceci,R.J.(2012),Br JHaematol,159: 299-310.
用于生成抗体的噬菌体展示和组合方法是本领域已知的(如例如,Ladner等人的美国专利号5,223,409;Kang等人的国际公开号WO 92/18619;Dower等人的国际公开号WO91/17271; Winter等人的国际公开号WO 92/20791;Markland等人的国际公开号WO 92/15679;Breitling 等人的国际公开WO 93/01288;McCafferty等人的国际公开号WO 92/15679 92/01047;Garrard 等人国际公开号WO 92/09690;Ladner等人国际公开号WO 90/02809;Fuchs et al.(1991) Bio/Technology 9:1370-1372;Hay et al.(1992)HumAntibod Hybridomas 3:81-85;Huse et al. (1989)Science 246:1275-1281;Griffthset al.(1993)EMBO J 12:725-734;Hawkins et al.(1992) J Mol Biol 226:889-896;Clackson et al.(1991)Nature 352:624-628;Gram et al.(1992)PNAS 89:3576-3580;Garrad et al.(1991)Bio/Technology 9:1373-1377;Hoogenboom et al.(1991)Nuc AcidRes 19:4133-4137;以及Barbas et al.(1991)PNAS 88:7978-7982中所描述的,其全部内容通过引用并入本文)。
在一些实施方式中,CD1a靶向部分是包含VL结构域和VH结构域的抗体、scFv、Fab或scFab,其中所述VL结构域包含LCDR1、LCDR2和LCDR3多肽以及所述VH结构域包含HCDR1、HCDR2和HCDR3多肽,并且LCDR1由[QDINKY](SEQ ID NO:1)组成, LCDR2由[YTS]组成,LCDR3由[LHYDNLPWT](SEQ ID NO:3)组成,HCDR1由[GYAFSTYT] (SEQ ID NO:4)组成,HCDR2由[INPNSAST](SEQ ID NO:5)组成,以及HCDR3由 [ARGFYTMDY](SEQ ID NO:6)组成。
在一些实施方式中,CD1a靶向部分是包含VL结构域和VH结构域的scFv,其中所述VL结构域包含LCDR1、LCDR2和LCDR3多肽以及所述VH结构域包含HCDR1、HCDR2 和HCDR3多肽,并且LCDR1由[QDINKY](SEQ ID NO:1)组成,LCDR2由[YTS]组成,LCDR3由[LHYDNLPWT](SEQ ID NO:3)组成,HCDR1由[GYAFSTYT](SEQ ID NO: 4)组成,HCDR2由[INPNSAST](SEQID NO:5)组成,以及HCDR3由[ARGFYTMDY] (SEQ ID NO:6)组成。
在一些实施方式中,CD1a靶向部分是包含VL结构域和VH结构域的抗体、scFv、Fab或scFab,其中VL结构域由SEQ ID NO:7组成并且VH结构域由SEQ ID NO:8组成。
在一些实施方式中,CD1a靶向部分是包含VL结构域和VH结构域的scFv,其中VL结构域由SEQ ID NO:7组成并且VH结构域由SEQ ID NO:8组成。
VL结构域(SEQ ID NO:7)
[RDIQMTQSPSSLSASLGGKVTITCQASQDINKYIAWYQFKPGKGPRLLIHYTSTLQPAIP SRFSGSGSGREYSFSISNLEPEDIATYYCLHYDNLPWTFGGGTKLEIKRA]
VH结构域(SEQ ID NO:8)
[QVQLQQSGAELARPGASVKMSCKASGYAFSTYTMHWVKQRPRQGLEWIGYINPNSA STSYNENFKDKATLTADKSSNTAYMHLSSLTSEDSAVYYCARGFYTMDYWGQGTSVTVSS]
在一些实施方式中,CD1a靶向部分是包含SEQ ID NO:9或由SEQ ID NO:9组成的scFv。
源自克隆NA1/34.HLK(SEQ ID NO:9)的scFv
[QVQLQQSGAELARPGASVKMSCKASGYAFSTYTMHWVKQRPRQGLEWIGYINPNSA STSYNENFKDKATLTADKSSNTAYMHLSSLTSEDSAVYYCARGFYTMDYWGQGTSVTVSS GGGGSGGGGSGGGGSGGGGSRDIQMTQSPSSLSASLGGKVTITCQASQDINKYIAWYQFKP GKGPRLLIHYTSTLQPAIPSRFSGSGSGREYSFSISNLEPEDIATYYCLHYDNLPWTFGGGTKL EIKRA]
跨膜结构域
跨膜结构域可以源自天然或合成来源。当来源是天然的时,结构域可以源自任何膜结合蛋白或跨膜蛋白。跨膜区可以至少包含CD28、CD3、CD45、CD4、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137或CD154的α链、β链或ζ链的跨膜区。
跨膜结构域可以是合成的跨膜结构域,或天然存在的跨膜结构域的变体。在一些实施方式中,合成的或变异的跨膜结构域主要包含疏水性残基,例如亮氨酸和缬氨酸。
在一些实施方式中,跨膜结构域包括CD28、CD3、CD45、CD4、CD8、CD9、CD16、 CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154的跨膜结构域或其变体,其中,其变体具有95%的序列同一性。
在一些实施方式中,跨膜结构域包括CD28、CD3、CD45、CD4、CD8、CD9、CD16、 CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154的跨膜结构域或其变体,其中,其变体具有98%的序列同一性。
在一些实施方式中,跨膜结构域包含CD28、CD3、CD45、CD4、CD8、CD9、CD16、 CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137或CD154的跨膜结构域。
在一些实施方式中,跨膜结构域包含CD8的跨膜结构域或其变体,其中,其变体具有95%的序列同一性。
在一些实施方式中,跨膜结构域包含CD8的跨膜结构域或其变体,其中,其变体具有98%的序列同一性。
在一些实施方式中,跨膜结构域包含CD8的跨膜结构域。
在一些实施方式中,跨膜结构域包含SEQ ID NO:10或与SEQ ID NO:10具有95%序列同一性的序列。
在一些实施方式中,跨膜结构域包含SEQ ID NO:10或与SEQ ID NO:10具有98%序列同一性的序列。
在一些实施方式中,跨膜结构域包含SEQ ID NO:10。在一些实施方式中,跨膜结构域由SEQ ID NO:10组成。
源自CD8的跨膜结构域(SEQ ID NO:10)
[TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYC]
胞内信号传导结构域
胞内信号传导结构域在与肿瘤细胞上表达的配体结合后激活表达CAR的细胞的至少一种功能。在一些实施方式中,胞内信号传导结构域包含一个或多个胞内信号传导结构域。在一些实施方式中,胞内信号传导结构域是提供包含CAR的细胞的至少一种功能的激活的胞内信号传导结构域的一部分和/或变体。
在一些实施方式中,胞内信号传导结构域包括CD3ζ、FcRγ、CD3γ、CD3δ、CD3ε、CD5、 CD22、CD79a、CD79b、CD66b的胞内结构域或其变体,其中,其变体具有95%的序列同一性。
在一些实施方式中,胞内信号传导结构域包括CD3ζ、FcRγ、CD3γ、CD3δ、CD3ε、CD5、 CD22、CD79a、CD79b、CD66b的胞内结构域或其变体,其中,其变体具有98%的序列同一性。
在一些实施方式中,胞内信号传导结构域包含CD3ζ、FcRγ、CD3γ、CD3δ、CD3ε、CD5、 CD22、CD79a、CD79b或CD66b的胞内结构域。
在一些实施方式中,胞内信号传导结构域包含CD3ζ的胞内结构域或其变体,其中,其变体具有95%的序列同一性。
在一些实施方式中,胞内信号传导结构域包含CD3ζ的胞内结构域或其变体,其中,其变体具有98%的序列同一性。
在一些实施方式中,胞内信号传导结构域包含CD3ζ的胞内结构域。
在一些实施方式中,胞内信号传导结构域包含SEQ ID NO:11或与SEQ ID NO:11具有95%序列同一性的序列。
在一些实施方式中,胞内信号传导结构域包含SEQ ID NO:11或与SEQ ID NO:11具有98%序列同一性的序列。
在一些实施方式中,胞内信号传导结构域包含SEQ ID NO:11或与SEQ ID NO:11具有99%序列同一性的序列。
在一些实施方式中,胞内信号传导结构域包含SEQ ID NO:11。在一些实施方式中,胞内信号传导结构域由SEQ ID NO:11组成。
源自CD3ζ的胞内信号传导结构域(SEQ ID NO:11)
[RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQ EGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR]
共刺激信号传导结构域
在一些实施方式中,CAR还可以包括共刺激信号传导结构域。在一些实施方式中,共刺激信号传导结构域包含CD27、CD28、CD137、CD134、CD30、CD40、淋巴细胞功能相关抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C、CD276的胞内结构域或其变体,其中,其变体具有95%的序列同一性。
在一些实施方式中,共刺激信号传导结构域包含CD27、CD28、CD137、CD134、CD30、CD40、淋巴细胞功能相关抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C、CD276的胞内结构域或其变体,其中,其变体具有98%的序列同一性。
在一些实施方式中,共刺激信号传导结构域包含CD27、CD28、CD137、CD134、CD30、CD40、淋巴细胞功能相关抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C或CD276的胞内结构域。
在一些实施方式中,共刺激信号传导结构域包含CD137的胞内结构域或其变体,其中,其变体具有95%的序列同一性。
在一些实施方式中,共刺激信号传导结构域包含CD137的胞内结构域或其变体,其中,其变体具有98%的序列同一性。
在一些实施方式中,共刺激信号传导结构域包含CD137的胞内结构域。
在一些实施方式中,共刺激信号传导结构域包含SEQ ID NO:12或与SEQ ID NO:12具有95%序列同一性的序列。
在一些实施方式中,共刺激信号传导结构域包含SEQ ID NO:12或与SEQ ID NO:12具有98%序列同一性的序列。
在一些实施方式中,共刺激信号传导结构域包含SEQ ID NO:12或与SEQ ID NO:12具有99%序列同一性的序列。
在一些实施方式中,共刺激信号传导结构域包含SEQ ID NO:12。在一些实施方式中,共刺激信号传导结构域由SEQ ID NO:12组成。
源自CD137的共刺激信号传导结构域(SEQ ID NO:12)
[KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL]
根据本发明的全序列CAR
在一些实施方式中,CAR包括:
(i)包含VL结构域和VH结构域的scFv,其中所述VL结构域包含LCDR1、LCDR2 和LCDR3多肽以及所述VH结构域包含HCDR1、HCDR2和HCDR3多肽,并且LCDR1由 [QDINKY](SEQID NO:1)组成,LCDR2由[YTS]组成,LCDR3由[LHYDNLPWT](SEQ ID NO:3)组成,HCDR1由[GYAFSTYT](SEQ ID NO:4)组成,HCDR2由[INPNSAST] (SEQ ID NO:5)组成,以及HCDR3由[ARGFYTMDY](SEQ ID NO:6)组成;
(ii)跨膜结构域,该跨膜结构域包含SEQ ID NO:10或与SEQ ID NO:10具有95%序列同一性的序列;
(iii)胞内信号传导结构域,该胞内信号传导结构域包含SEQ ID NO:11或与SEQID NO:11具有95%序列同一性的序列;和
(iv)共刺激信号传导结构域,该共刺激信号传导结构域包含SEQ ID NO:12或与SEQ ID NO:12具有95%序列同一性的序列。
在一些实施方式中,CAR包括:
(i)包含VL结构域和VH结构域的scFv,其中所述VL结构域包含LCDR1、LCDR2 和LCDR3多肽以及所述VH结构域包含HCDR1、HCDR2和HCDR3多肽,并且LCDR1由 [QDINKY](SEQID NO:1)组成,LCDR2由[YTS]组成,LCDR3由[LHYDNLPWT](SEQ ID NO:3)组成,HCDR1由[GYAFSTYT](SEQ ID NO:4)组成,HCDR2由[INPNSAST] (SEQ ID NO:5)组成,以及HCDR3由[ARGFYTMDY](SEQ ID NO:6)组成;
(ii)跨膜结构域,该跨膜结构域包含SEQ ID NO:10或与SEQ ID NO:10具有98%序列同一性的序列;
(iii)胞内信号传导结构域,该胞内信号传导结构域包含SEQ ID NO:11或与SEQID NO:11具有98%序列同一性的序列;和
(iv)共刺激信号传导结构域,该共刺激信号传导结构域包含SEQ ID NO:12或与SEQ ID NO:12具有98%序列同一性的序列。
在一些实施方式中,CAR包括:
(i)包含VL结构域和VH结构域的scFv,其中所述VL结构域包含LCDR1、LCDR2 和LCDR3多肽以及所述VH结构域包含HCDR1、HCDR2和HCDR3多肽,并且LCDR1由 [QDINKY](SEQID NO:1)组成,LCDR2由[YTS]组成,LCDR3由[LHYDNLPWT](SEQ ID NO:3)组成,HCDR1由[GYAFSTYT](SEQ ID NO:4)组成,HCDR2由[INPNSAST] (SEQ ID NO:5)组成,以及HCDR3由[ARGFYTMDY](SEQ ID NO:6)组成;
(ii)跨膜结构域,该跨膜结构域包含SEQ ID NO:10或与SEQ ID NO:10具有98%序列同一性的序列;
(iii)胞内信号传导结构域,该胞内信号传导结构域包含SEQ ID NO:11或与SEQID NO:11具有99%序列同一性的序列;和
(iv)共刺激信号传导结构域,该共刺激信号传导结构域包含SEQ ID NO:12或与SEQ ID NO:12具有99%序列同一性的序列。
在一些实施方式中,CAR包括:
(i)包含VL结构域和VH结构域的scFv,其中所述VL结构域包含LCDR1、LCDR2 和LCDR3多肽以及所述VH结构域包含HCDR1、HCDR2和HCDR3多肽,并且LCDR1由 [QDINKY](SEQID NO:1)组成,LCDR2由[YTS]组成,LCDR3由[LHYDNLPWT](SEQ ID NO:3)组成,HCDR1由[GYAFSTYT](SEQ ID NO:4)组成,HCDR2由[INPNSAST] (SEQ ID NO:5)组成,以及HCDR3由[ARGFYTMDY](SEQ ID NO:6)组成;
(ii)包含SEQ ID NO:10的跨膜结构域;
(iii)包含SEQ ID NO:11的胞内信号传导结构域;和
(iv)包含SEQ ID NO:12的共刺激信号传导结构域。
在一些实施方式中,CAR包括:
(i)包含VL结构域和VH结构域的scFv,其中所述VL结构域包含LCDR1、LCDR2 和LCDR3多肽以及所述VH结构域包含HCDR1、HCDR2和HCDR3多肽,并且LCDR1由 [QDINKY](SEQID NO:1)组成,LCDR2由[YTS]组成,LCDR3由[LHYDNLPWT](SEQ ID NO:3)组成,HCDR1由[GYAFSTYT](SEQ ID NO:4)组成,HCDR2由[INPNSAST] (SEQ ID NO:5)组成,以及HCDR3由[ARGFYTMDY](SEQ ID NO:6)组成;
(ii)由SEQ ID NO:10组成的跨膜结构域;
(iii)由SEQ ID NO:11组成的胞内信号传导结构域;和
(iv)由SEQ ID NO:12组成的共刺激信号传导结构域。
在一些实施方式中,CAR包括:
(i)包含VL结构域和VH结构域的scFv,其中VL结构域由SEQ ID NO:7组成并且 VH结构域由SEQ ID NO:8组成;
(ii)跨膜结构域,该跨膜结构域包含SEQ ID NO:10或与SEQ ID NO:10具有95%序列同一性的序列;
(iii)胞内信号传导结构域,该胞内信号传导结构域包含SEQ ID NO:11或与SEQID NO:11具有95%序列同一性的序列;和
(iv)共刺激信号传导结构域,该共刺激信号传导结构域包含SEQ ID NO:12或与SEQ ID NO:12具有95%序列同一性的序列。
在一些实施方式中,CAR包括:
(i)包含VL结构域和VH结构域的scFv,其中VL结构域由SEQ ID NO:7组成并且 VH结构域由SEQ ID NO:8组成;
(ii)跨膜结构域,该跨膜结构域包含SEQ ID NO:10或与SEQ ID NO:10具有98%序列同一性的序列;
(iii)胞内信号传导结构域,该胞内信号传导结构域包含SEQ ID NO:11或与SEQID NO:11具有98%序列同一性的序列;和
(iv)共刺激信号传导结构域,该共刺激信号传导结构域包含SEQ ID NO:12或与SEQ ID NO:12具有98%序列同一性的序列。
在一些实施方式中,CAR包括:
(i)包含VL结构域和VH结构域的scFv,其中VL结构域由SEQ ID NO:7组成并且 VH结构域由SEQ ID NO:8组成;
(ii)跨膜结构域,该跨膜结构域包含SEQ ID NO:10或与SEQ ID NO:10具有98%序列同一性的序列;
(iii)胞内信号传导结构域,该胞内信号传导结构域包含SEQ ID NO:11或与SEQID NO:11具有99%序列同一性的序列;和
(iv)共刺激信号传导结构域,该共刺激信号传导结构域包含SEQ ID NO:12或与SEQ ID NO:12具有99%序列同一性的序列。
在一些实施方式中,CAR包括:
(i)包含VL结构域和VH结构域的scFv,其中VL结构域由SEQ ID NO:7组成并且 VH结构域由SEQ ID NO:8组成;
(ii)包含SEQ ID NO:10的跨膜结构域;
(iii)包含SEQ ID NO:11的胞内信号传导结构域;和
(iv)包含SEQ ID NO:12的共刺激信号传导结构域。
在一些实施方式中,CAR包括:
(i)包含VL结构域和VH结构域的scFv,其中VL结构域由SEQ ID NO:7组成并且VH结构域由SEQ ID NO:8组成;
(ii)由SEQ ID NO:10组成的跨膜结构域;
(iii)由SEQ ID NO:11组成的胞内信号传导结构域;和
(iv)由SEQ ID NO:12组成的共刺激信号传导结构域。
在一些实施方式中,CAR包含以下序列或由以下序列组成:SEQ ID NO:2或与SEQID NO:2具有95%序列同一性的序列。在一些实施方式中,CAR包含以下序列或由以下序列组成:SEQ ID NO:2或与SEQ ID NO:2具有98%序列同一性的序列。在一些实施方式中, CAR包含以下序列或由以下序列组成:SEQ ID NO:2或与SEQ ID NO:2具有99%序列同一性的序列。在一些实施方式中,CAR包含SEQ ID NO:2或由SEQ ID NO:2组成。
CAR的全序列(SEQ ID NO:2)
[MALPVTGLLLSLGLLLHAARPTGQVQLQQSGAELARPGASVKMSCKASGYAFSTYT MHWVKQRPRQGLEWIGYINPNSASTSYNENFKDKATLTADKSSNTAYMHLSSLTSEDSAVY YCARGFYTMDYWGQGTSVTVSSGGGGSGGGGSGGGGSGGGGSRDIQMTQSPSSLSASLG GKVTITCQASQDINKYIAWYQFKPGKGPRLLIHYTSTLQPAIPSRFSGSGSGREYSFSISNLEP EDIATYYCLHYDNLPWTFGGGTKLEIKRATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGA VHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEM GGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDA LHMQALPPR]
核酸
一方面,本发明提供了编码本发明的任一种CAR(包括上文公开的任一种CAR)的核酸。编码嵌合受体的核酸序列将许多模块化组件连接在一起,这些组件可以被切除并替换为其他组件,以便定制嵌合受体以有效活化T细胞并识别CD1a。
在一些实施方式中,核酸适用于转导或转化细胞。在一些实施方式中,核酸适用于转导或转化用于过继免疫疗法的T细胞。
在一些实施方式中,核酸是针对在哺乳动物细胞中表达而优化的密码子。密码子优化方法是本领域已知的(参见,例如,Parret et al.,2016.Curr Opin Struct Biol.39:155-162)。
本发明的核酸可以包含在可用于转导或转化T细胞的γ-逆转录病毒或慢病毒运载体中 (参见Rivière&Sadelain,2017.Mol Ther.25(5):1117-1124)。也可以通过使用DNA转座子、 RNA转染或基因组编辑技术(例如,TALEN、ZFN和CRISPR/Cas9)将核酸插入细胞中(参见Rivière&Sadelain,2017.Mol Ther.25(5):1117-1124)。
细胞
在一个方面,本发明提供包含本发明的核酸和/或本发明的CAR的细胞。在一些实施方式中,细胞是T细胞(称为CART)。
在一些实施方式中,细胞是幼稚T细胞、记忆干T细胞或中枢记忆T细胞。目前认为这些细胞更适合于适应性免疫疗法(参见Rivière&Sadelain,2017.Mol Ther.25(5):1117-1124)。
在一些实施方式中,细胞是自体T细胞。术语“自体细胞”是指从要使用本发明的任何一种方法治疗的同一患者中获得的细胞。值得注意的是,对获得自40名具有活性T细胞急性淋巴母细胞白血病的患者的外周血的流式细胞术分析显示,所有患者中都存在正常的CD3+CD1a-T细胞。因此,完全有可能使用包含本发明的核酸和/或CAR的自体T细胞来治疗患者。
在一些实施方式中,细胞是同种异体耐受T细胞。术语“同种异体耐受细胞”是指经工程改造以降低发生移植物抗宿主病反应风险的细胞。在一些实施方式中,这是通过基因组编辑介导的TCR和/或β2-微球蛋白缺失来实现的15,19。同种异体耐受细胞是本领域已知的(参见 Rivière&Sadelain,2017.Mol Ther.25(5):1117-1124中的同种异体耐受T细胞部分)。
在一些实施方式中,T细胞是CD3阳性和CD1a阴性T细胞。
在一些实施方式中,细胞是具有分化为成熟T细胞的能力的淋巴前体、胚胎干细胞或诱导多能干细胞(参见Rivière&Sadelain,2017.Mol Ther.25(5):1117-1124)。
药物组合物
在一个方面,本发明提供了包含本发明的多个细胞和药学上可接受的载体或稀释剂的药物组合物。
本文所述的药物组合物还可以含有其他物质。这些物质包括但不限于冷冻保护剂、表面活性剂、抗氧化剂和稳定剂。本文所用的术语“冷冻保护剂”包括为CART提供抗冰冻诱导的应力的稳定性的试剂。冷冻保护剂的非限制性实例包括:糖,例如蔗糖、葡萄糖、海藻糖、甘露醇、甘露糖和乳糖;聚合物,例如右旋糖酐、羟乙基淀粉和聚乙二醇;表面活性剂,例如聚山梨酸酯(例如,PS-20或PS-80);以及氨基酸,例如甘氨酸、精氨酸、亮氨酸和丝氨酸。通常使用在生物系统中表现出低毒性的冷冻保护剂。
在一些实施方式中,通过首先从细胞的培养基中收获细胞,然后在适合于以治疗有效量施用的培养基和容器系统(“药学上可接受的”载体)中洗涤并浓缩细胞来配制细胞。合适的输注介质可以是任何等渗介质制剂,通常是生理盐水、Normosol R(Abbott)或Plasma-Lyte A(Baxter),但也可以使用5%葡萄糖水溶液或林格氏(Ringer's)乳酸盐。输注介质可以补充人血清白蛋白、胎牛血清或其他人血清成分。
在一个方面,本发明提供了用作药物的根据本发明的细胞或根据本发明的药物组合物。
治疗方法
在一个方面,本发明提供了一种治疗CD1a阳性癌症的方法,该方法包括向有需要的患者施用本发明的细胞或本发明的药物组合物。
在一些实施方式中,对患者施用治疗有效量的细胞。在一些实施方式中,对患者施用至少102、103、104、105、106、107、108、109或1010个细胞。细胞的数量将取决于组合物的最终用途以及其中包含的细胞类型。例如,如果需要对特定抗原具有特异性的细胞,则该群体将包含大于70%,通常大于80%、85%和90%至95%的这种细胞。对于本文提供的用途,细胞的体积通常为一升或更小,可以为500ml或更小,甚至250ml或更小,或100ml或更小。临床相关的细胞数可以分配到累积等于或超过102、103、104、105、106、107、108、109或1010个细胞的多次输注中。
在一些实施方式中,细胞或药物组合物被静脉内、腹膜内施用到骨髓、淋巴结和/或脑脊液中。
在一些实施方式中,该方法包括组合疗法。在一些实施方式中,该方法包括进一步施用免疫检查点抑制剂(参见Lim&June,2017.Cell.168(4):724-740)。在进一步的实施方式中,该方法包括进一步施用免疫检查点抑制剂和/或IAP抑制剂(参见WO 2016/054555))。
在一些实施方式中,如本文所述的细胞或药物组合物与化疗剂和/或免疫抑制剂组合施用。在一个实施方式中,首先用抑制或破坏其他免疫细胞的化疗剂治疗患者,然后用本文所述的细胞或药物组合物治疗。在某些情况下,可以完全避免化疗。
在一些实施方式中,CD1a阳性癌症是皮质T细胞急性淋巴母细胞白血病或朗格汉斯细胞组织细胞增生症。在一些实施方式中,CD1a阳性癌症是皮质T细胞急性淋巴母细胞白血病。在一些实施方式中,CD1a阳性癌症是复发性/难治性皮质T细胞急性淋巴母细胞白血病。
一般来说,白血病的复发可在初次缓解后数月或数年表现出来;然而,大多数复发发生在初始治疗后的两年内。难治性是表示患者在复发后对至少一种治疗策略不再有反应的术语。
在ALL的一线试验中存在广泛共识,特别是在成人中,复发被定义为“在先前实现完全缓解(CR)或明确证明髓外白血病参与后骨髓中检测到超过5%的原始细胞”(参见 (2017))。欧洲成人ALL工作组(European Working Group on Adult ALL,EWALL)在一项共识建议中记录了这一声明(参见Dohner(2010)),并附加解释说“在强化治疗阶段期间和/或再生期间的某个阶段有5%至20%的原始细胞,则应在一周后重复评估骨髓,以区分骨髓复发和再生现象”。引用的定义基于急性髓系白血病的结局参数的国际建议(参见Cheson(2003)和 Chantepie(213));这已被外推到ALL的几个亚型,如T-ALL的情况。
最近,一些试验甚至没有定义复发的概念。因此,嵌合抗原受体(CAR)T细胞的研究包括患有“可测量疾病”的患者,也包括患有血液学复发(无额外说明)或微小残留病(Minimal residual disease,MRE)的患者(参见Lee(2015)和Maude(2014)和(2017))。请参阅:
·Dohner H,Estey EH,Amadori S,et al,Diagnosis and management of acutemyeloid leukemia in adults:recommendations from an international expertpanel,on behalf of the European Leukemia Net.Blood 2010;115:453–74.
·Cheson BD,Bennett JM,Kopecky KJ,et al.Revised recommendations ofthe International Working Group for Diagnosis,Standardization of ResponseCriteria,Treatment Outcomes,and Reporting Standards for Therapeutic Trials inAcute Myeloid Leukemia.J Clin Oncol 2003;21:4642- 9.
·Chantepie SP,Cornet E,Salaun V,Reman O.Hematogones:an overview.LeukRes 2013;37:1404–11.
·13.Maude SL,Frey N,Shaw PA,et al.Chimeric antigen receptor T cellsfor sustained remissions in leukemia.N Engl J Med 2014;371:1507–17.
·N,Dombret H,Bassan R,Wadleigh M,Doubek M,Ribera J.Inclusionand response criteria for clinical trials in relapsed/refractory acutelymphoblastic leukemia and usefulness of historical controltrials.Haematologica.2017;102(3):e118–e119。
在一些实施方式中,要用本发明的方法治疗的患者在用另一种疗法治疗后处于完全缓解或接近完全缓解。在使用本发明的方法之前降低肿瘤负荷可能是优选的,因为在患者具有高度活跃的复发性/难治性皮质T细胞急性淋巴母细胞白血病的的情况下存在若干种替代的效应T细胞。在一些实施方式中,用本发明的方法治疗的患者先前已用另一种疗法治疗,该疗法导致部分响应、完全响应、稳定疾病、进展性疾病减少、肿瘤进展时间缩短或其任何组合。
实施例
材料和方法
CD1a特异性scFv生成和CAR设计
使用商业合成(Sigma-Aldrich)用小鼠IgG文库引物集(Progen)获得源自CD1a特异性抗体的NA1/34.HLK克隆的CD1a特异性单链可变片段(scFv),并克隆到基于pCCL慢病毒的第二代CAR骨架中,该第二代CAR骨架包含人CD8跨膜(TM)结构域、人CD137和 CD3ζ内结构域以及T2A-GFP盒。单独表达GFP(空白运载体)或CD22 CAR骨架的相同慢病毒运载体用作对照(图1D和图8A)。
表达CAR的慢病毒产生、T细胞转导、活化和扩增
使用标准聚乙烯亚胺转染方案在293T细胞中生成用VSV-G拟型的表达CAR的病毒颗粒,并通过超速离心浓缩,如别处所描述的27。病毒滴度始终在108TU/mL范围内。通过Ficoll- Hypaque梯度离心从健康志愿者的血沉棕黄层中分离外周血单核细胞(Peripheral blood mononuclear cell,PBMC)。经IRB批准(HCB/2018/0030),从巴塞罗那血液和组织(Barcelona Blood and Tissue,BST)银行获得血沉棕黄层。T细胞被平板结合的抗CD3抗体(OKT3)和抗CD28抗体(BD Biosciences)活化2天,然后在白细胞介素7(interleukin-7,IL-7)和IL- 15(10ng/mL,Mitenyi Biotec)存在下用表达CAR的慢病毒(MOI=10)转导16,18。通过GFP 的荧光激活细胞分选(Fluorescence-activated cellsorting,FACS)共表达来追踪CD1aCAR的细胞表面表达,并使用AffiniPure F(ab')2片段山羊抗小鼠IgG(H+L)(Jackson ImmunoResearch) 进行确认。通过扩增2天后针对CD25和CD69染色来证明CAR转导的T细胞的正确活化。
健康CD34+祖细胞、T细胞和原发性T-ALL样本的免疫表型分析
在新鲜人胸腺、胎肝和骨髓(Bone marrow,BM)、脐带血和成人BM以及外周血(Peripheral blood,PB)中对CD1a抗原在CD34+干细胞/祖细胞(HSPC)、CD34+CD7+胸腺T细胞祖细胞和CD3+T细胞中的表达进行了前瞻性分析(n=3)。胚胎组织是根据先前描述28,29从怀孕 18至22周时流产的发育胚胎收集的,该胚胎是在知情同意和我们当地伦理和生物危害董事委员会批准(CMRBCEIC-26/2013)后从MRC/Wellcome Trust人类发育生物学资源获得的。经IRB批准(HCB/2018/0030)从BST获得新生儿和成人组织。原发性T-ALL样本和诊断免疫表型分析数据从当地医院Sant Joan de Den、Germans Trias i Pujol、和Santa Creui San Pau (西班牙巴塞罗那)获得。对于T-ALL原发性样本的免疫表型分析,使用了以下荧光染料缀合的单克隆抗体(MoAb):抗CD2-PE、CD7-FITC/PE、CD13-PerCP-Cy5.5、CD34-APC、CD3- PE、CD5-FITC、CD4-BV-421、CD8-APC-Cy7、CD45-AmCyan、CD1a-BV-421/APC/PE、CD33-APC和CD123-APC(BDBiosciencies或Miltenyi Biotec)。同种型匹配、非反应性荧光染料偶联的MoAb始终用作荧光参考。简而言之,将PB单核细胞(PBMC,约5×105个)与红细胞裂解液(BDBiosciencies)一起孵育10分钟,然后用MoAb染色(于4℃暗处中20min)。在磷酸盐缓冲盐水(Phosphate buffered saline,PBS)中洗涤染色的细胞,并在配备FACSDiva软件(BDBiosciencies)的FACSCanto-II流式细胞仪上通过FACS进行分析30-32。
体外细胞毒性测定和细胞因子释放测定
细胞系Jurkat、MOLT4和NALM6购自DSMZ(德国布伦瑞克),并根据DSMZ的建议进行扩增。通过逆转录病毒转导和GFP+细胞的FACS纯化来稳定产生荧光素酶(Luc)/GFP 表达细胞33。靶细胞(细胞系和原发性T-ALL原始细胞)用3μM eFluor670(eBioscience)进行标记,并与CD1a、CD22或空白CART以不同的效靶(Effector:Target,E:T)比孵育指定的时间段。通过分析每个时间点的残留的活性(7-AAD-)eFluor670+靶细胞和E:T比来确定CART介导的细胞毒性。使用Trucount绝对计数珠(BDBiosciences)确定绝对细胞计数。此外,来自皮质T-ALL患者的PB的FACS分选的CD3+CD1a-成熟T细胞呈现为被激活,用 CD1a CAR进行转导,并针对其eFluor670标记的自体CD1a+T-ALL原始细胞进行测试。在 16小时后收获的上清液中,通过ELISA(人ELISA SET,BDBiosciences)测量促炎细胞因子 IL-2、TNFα和IFNγ的产生。
体内Jurkat和T-ALL患者来源的异种移植(Patient-derived xenograft,PDX)模型
在巴塞罗那生物医学研究园(Barcelona Biomedical Research Park,PRBB)的动物设施中在无病原体条件下饲养和安置6周龄至12周龄的非肥胖糖尿病(Nonobesediabetic,NOD) -Cg-Prkdcscid Il2rgtm1Wjl/SzJ(NSG)小鼠(杰克逊实验室(The JacksonLaboratory))。对小鼠进行辐照(2Gy)和用3×106个表达Luc-GFP的Jurkat细胞或1×106个原发性皮质CD1a+ T-ALL原始细胞(原发性和原发性移植物扩增)进行静脉内(i.v.)移植34。3天后静脉内输注1.5×106至5×106个CD1a或空白CART。当使用Luc-Jurkat细胞时,使用Xenogen IVIS 50 成像系统(Perkin Elmer)通过生物发光(Bioluminescence,BLI)跟踪肿瘤负荷。为了测量发光,小鼠腹膜内接受150mg/kg的D-荧光素,并在指定的时间点监测肿瘤负荷。Living Image 软件(Perkin Elmer)用于可视化和计算总发光。通过每两周一次的出血和FACS分析对原发性T-ALL样本的肿瘤负荷进行随访。当空白CART治疗的动物出现白血病时处死小鼠,并通过FACS在BM、PB和脾脏中分析肿瘤负荷(hHLA-ABC+hCD45+hCD1a+移植物)和CART 持续性(hHLA-ABC+hCD45+hCD3+hCD1a-GFP+)。在再次攻击实验中,对在5周至6周前接受过CD1a CART输注的无白血病动物再次输注1.5×106个Luc-Jurkat细胞或1×106个CD1a+ T-ALL原发性移植物,并通过BLI和FACS随访疾病复发,如上所述。所有程序均遵照PRBB 的机构动物护理和使用委员会进行(DAAM7393)。
酶联免疫斑点试验(Enzyme-linked immunospot assay,ELISpot)
用抗人IFNγ抗体(1-D1K,Mabtech)涂覆ELISpot板(Millipore),并在4℃下保持过夜。然后将板用含有1%胎牛血清的PBS洗涤六次,然后将来自三个独立供体的细胞以5×105个至1×106个细胞/孔接种,并在37℃和5%CO2下以一式三份培养20小时。我们测量了IFNγ分泌细胞对1μg/mL的CEF(即1μg/mL的巨细胞病毒(Cytomegalovirus,CMV)、Epstein-Barr 病毒(Epstein-Barr virus,EBV)和流感的T细胞表位的肽池)的反应,以及对作为阳性对照的1μg/mL葡萄球菌肠毒素B(staphylococcal enterotoxin B,SEB)的反应。然后将平板暴露于生物素化的抗人IFNγ、链霉亲和素-碱性磷酸酶(Mabtech),如前所述35,36。使用ImmunoCapture和ImmunoSpot软件对IFNγ分泌细胞的频率进行量化,以计算每105的IFNγ斑点形成单位的数目(SFU)。
统计分析
所有图中都示出了来自至少三个个体供体的数据,并总是进行实验重复。在每种体内条件下使用至少五只动物。所有p值均使用Prism软件(GraphPad)通过未配对的双尾学生t检验来计算。使用Mantle-Cox检验确定小鼠的无事件生存期(EFS)。p值<0.05被认为具有统计学意义。
实施例1:CD1a特异性标记皮质T-ALL原始细胞
由于与CART相关的相残和潜在的危及生命的T细胞发育不全,CART和T系原始细胞之间靶抗原的共同表达限制了T-ALL中的免疫治疗方法。然而,CD1a抗原在皮质T-ALL(T-ALL的一个主要亚类)中表达(图1A、图1B),但在所有胸腺外组织的功能性T细胞中完全不存在25,并且稳态CD34+HSPC缺乏在个体发育的多个造血位点中的CD1a表达(图1C)。 T细胞发育通过首先定植具有淋巴髓样潜能的CD34高CD7-CD1a-原始HSPC在胸腺内启动,然后响应于胸腺微环境分化为CD34高CD7+CD1a-早期T细胞祖细胞37。随着它们通过胸腺分化而进展,T细胞祖细胞维持CD7表达并逐渐失去CD34表达,而CD1a表达出现并短暂地局限于皮质胸腺细胞38(图1E、图1F)。在CD34+胸腺群体中,约50%以皮质前T细胞祖细胞(CD34高CD7+CD1a-、图1E、图1F(灰色细胞))为代表,这使我们假设CD1a可能是用于本具有灾难性结果3,39-41的R/R皮质T-ALL的免疫治疗的可行且安全的靶标。
实施例2:重定向CD1a的T细胞(CD1a
CART)在没有T细胞相残的情况下扩增
我们设计了第二代CD1a CAR,其由抗CD1a scFv、CD8 TM间隔区、以及来自4-1BB(CD137)和通过T2A序列与GFP框内偶联的CD3ζ的胞内信号传导结构域组成(图2A)。在293T细胞(图2B)和在原发性CD4+和CD8+T细胞亚群(图2C)中,通过scFv和GFP 的共表达,很容易检测到CD1a CAR的表达。重要的是,活化的(CD69+CD25+)CD1a CART (图2D)在12天的时间内持续扩增了200倍,类似于空白T细胞(图2E),验证了将CART 重定向到CD1a抗原不会诱导T细胞相残。
实施例3:CD1a CART在体外特异性地根除T-ALL细胞系和原发性原始细胞
然后使用CD1a+T-ALL细胞系Jurkat和MOLT4以及作为阴性对照的B-ALL细胞系NALM6在体外对CD1a CART进行测试(图2F)。与对照CART(空白T细胞或CD22 CART) 相比,CD1a CART以依赖于E:T比的方式特异性消除CD1a+T-ALL细胞。在16小时测定中,2:1或4:1的相对低的E:T比诱导了50%至80%的特异性细胞裂解(图2H、图2I、图9)。重要的是,在1:1的E:T比下的72小时检测中,几乎没有任何CD1a+T-ALL细胞在暴露于 CD1a CART中存活下来(图2I)。CD1a CART在与CD1a+T-ALL细胞共培养时产生了高水平的促炎细胞因子IL-2、TNFα和IFNγ(图2K),证实了它们的作用。
为了进一步解决它们消除原发性肿瘤的能力,CD1a CART与原发性皮质T-ALL样本(新鲜采集的或PDX衍生的)共培养,CD1a+原始细胞的比例为80%至98%(图3A)。与空白T细胞相比,CD1a CART在72小时细胞毒性试验中以4:1的E:T比特异性消除了原发性CD1a+皮质T-ALL细胞(图3B、图3C)。与CD1a+T-ALL原始细胞共存于BM中的正常造血细胞 (CD1a-)不会被CD1a CART裂解(图3C)。与CD1a+原发性T-ALL细胞共培养时也分泌高水平的IFNγ和TNFα(图3D)。总的来说,这些结果表明CD1a CART在体外对T-ALL细胞系和原发性原始细胞具有有效和特异性的抗白血病活性。
实施例4:CD1a CART在体内显示出有效的抗白血病活性
我们接下来使用表达Luc的Jurkat T-ALL细胞(图4、图10)和原发性皮质T-ALL异种移植模型34(图5)评估了体内CD1a CART的活性。在静脉内输注2×106个或5×106个CD1a(或MOCK)CART的三天前,NSG小鼠被移植了3×106个表达Luc的Jurkat细胞。通过BLI 每周随访白血病的发生(图4A、图10)。与通过BLI显示出大量的肿瘤负荷的接受MOCK T 细胞的小鼠相比,接受CD1a CART的小鼠在第25天时几乎没有白血病(图4B、图4C、图 10)。白血病进展的控制是CD1a CART细胞剂量依赖性的(图10B、图10C)。处死时PB中肿瘤负荷的流式细胞术分析证实了BLI数据(图4D)。重要的是,FACS分析揭示了所分析的所有造血组织中的T细胞持续性(图4E);然而,与接受MOCK T细胞的小鼠中的T细胞生物分布相比,我们发现CD1a CART在BM和脾脏中的生物分布显著增加(图4E),这表明 CD1a CART对播散性白血病的主动控制。
在皮质T-ALL的临床上更相关的PDX模型中,首先将NSG小鼠移植1×106个原发性CD1a+T-ALL原始细胞,然后三天后输注1×106个CD1a(或MOCK)CART,然后通过出血和终点BM分析对白血病移植进行每两周随访(图5A)。CD1a+皮质T-ALL细胞的移植在 MOCK T细胞处理的PDX的BM(图5B,第6周和第9周分别为50%±13%和55%±11%) 和PB(图5C,第6周和第9周分别为4.4%±2%和18%±6%)中随着时间的推移逐渐增加,并且与第9周OS显著降低(42%对比100%,p=0.01;图5D)相关。相比之下,CD1a CART 完全消除了T-ALL生长/移植(BM和PB中的T-ALL原始细胞分别为0.36%和0%),并且它们在9周后在BM和PB中持续存在(图5B、图5C、图5E)。
实施例5:体内持续性CD1a CART在再次攻击试验中发挥作用
由于CART在造血组织中的持续性是其临床成功的主要生物学参数,所以我们接下来评估了持续40天至50天后的CD1a CART在控制T-ALL进展方面是否仍然起作用和有效。为此,将CD1a CART治疗后白血病消失的T-ALL移植小鼠用Luc-Jurkat细胞(图6A至图6D) 或来自原发性移植物的原发性T-ALL(图6E至图6G)再次攻击。与继发性白血病迅速(快至2周后)并大量移植的对照相比,在6周后的Jurkat(图6C)或原发性移植模型(图6F) 中,通过BLI或FACS几乎无法检测到T-ALL移植)。
实施例6:源自患者的CD1a CART特异性靶向自体CD1a+原始细胞并保留抗病毒活
性
正确选择靶抗原并避免T细胞相残对于CART治疗T-ALL成功至关重要。因此,我们检查了来自皮质T-ALL患者的源自PB的CD3+CD1a-T细胞是否可以被分离并进行遗传修饰以表达CD1a CAR(图7)。因此,将来自患者的CD3+CD1a-T细胞分离(>95%纯度,数据未显示),用CD3/CD28活化并用CD1a CAR或MOCK进行慢病毒转导(31%至70%转导)。接下来,我们研究了源自原发性T-ALL的CD1a CART对活性T-ALL患者匹配的PBMC的细胞溶解能力(图7A)。总PBMC被用作靶标,因为它使我们能够评估自体细胞毒性潜力和相残的程度。在eFluor670标记的靶PBMC中,绝大多数是CD1a+原始细胞,以及~15%是 CD3+CD1a-正常T细胞(图7B)。与MOCK T细胞相比,CD1a CART对自体CD1a+原始细胞显示出大规模且特异性的细胞溶解能力,但对CD1a-正常T细胞则没有(图6B),这进一步证明了CD1a CART具有抗相残性。
为了进一步评估CD1a CART的潜在胸腺毒性,我们接下来使用人正常胎儿胸腺衍生的 CD7+胸腺细胞作为靶细胞。CD1a CART仅消除了CD1a+皮质胸腺细胞(第二个和第三个灰色框),而发育较早和较晚的CD1a-(第一个框)胸腺T系群体(CD7+CD34+和CD7+CD34-) 没有被靶向(图1E、图1F),这将中靶/脱瘤效应限制在皮质胸腺细胞的发育瞬态胸腺群。我们最终试图确定CD1a CART是否可以通过靶向导致免疫抑制患者病毒血症的最常见病原体来独力地保护宿主。为此,我们测试了CD1a CART对CMV、EBV和Flu抗原(CEF)的反应性,并通过IFNγELISpot量化了SCF。MOCK T细胞和CD1a CART对用病毒肽刺激的反应非常相似,表明了CD1a CART保留了抗病毒活性(图7D)。
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序列表
<110> 约瑟夫卡雷拉斯白血病研究基金会(IJC)
加泰罗尼亚高等研究院(ICREA)
<120> 用于治疗CD1a阳性癌症的CAR T细胞
<130> 904 873
<160> 12
<170> BiSSAP 1.3.6
<210> 1
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> LCDR1
<400> 1
Gln Asp Ile Asn Lys Tyr
1 5
<210> 2
<211> 493
<212> PRT
<213> Artificial Sequence
<220>
<223> Full sequence of the CAR
<400> 2
Met Ala Leu Pro Val Thr Gly Leu Leu Leu Ser Leu Gly Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Thr Gly Gln Val Gln Leu Gln Gln Ser Gly Ala
20 25 30
Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser
35 40 45
Gly Tyr Ala Phe Ser Thr Tyr Thr Met His Trp Val Lys Gln Arg Pro
50 55 60
Arg Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Asn Ser Ala Ser
65 70 75 80
Thr Ser Tyr Asn Glu Asn Phe Lys Asp Lys Ala Thr Leu Thr Ala Asp
85 90 95
Lys Ser Ser Asn Thr Ala Tyr Met His Leu Ser Ser Leu Thr Ser Glu
100 105 110
Asp Ser Ala Val Tyr Tyr Cys Ala Arg Gly Phe Tyr Thr Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg
145 150 155 160
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
165 170 175
Gly Lys Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Asn Lys Tyr
180 185 190
Ile Ala Trp Tyr Gln Phe Lys Pro Gly Lys Gly Pro Arg Leu Leu Ile
195 200 205
His Tyr Thr Ser Thr Leu Gln Pro Ala Ile Pro Ser Arg Phe Ser Gly
210 215 220
Ser Gly Ser Gly Arg Glu Tyr Ser Phe Ser Ile Ser Asn Leu Glu Pro
225 230 235 240
Glu Asp Ile Ala Thr Tyr Tyr Cys Leu His Tyr Asp Asn Leu Pro Trp
245 250 255
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Thr Thr Thr
260 265 270
Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro
275 280 285
Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val
290 295 300
His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro
305 310 315 320
Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu
325 330 335
Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro
340 345 350
Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys
355 360 365
Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe
370 375 380
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
385 390 395 400
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
405 410 415
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg
420 425 430
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
435 440 445
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
450 455 460
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
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Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
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<210> 3
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
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Leu His Tyr Asp Asn Leu Pro Trp Thr
1 5
<210> 4
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
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<400> 4
Gly Tyr Ala Phe Ser Thr Tyr Thr
1 5
<210> 5
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> HCDR2
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Ile Asn Pro Asn Ser Ala Ser Thr
1 5
<210> 6
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> HCDR3
<400> 6
Ala Arg Gly Phe Tyr Thr Met Asp Tyr
1 5
<210> 7
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> VL domain
<400> 7
Arg Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu
1 5 10 15
Gly Gly Lys Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Asn Lys
20 25 30
Tyr Ile Ala Trp Tyr Gln Phe Lys Pro Gly Lys Gly Pro Arg Leu Leu
35 40 45
Ile His Tyr Thr Ser Thr Leu Gln Pro Ala Ile Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Arg Glu Tyr Ser Phe Ser Ile Ser Asn Leu Glu
65 70 75 80
Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Leu His Tyr Asp Asn Leu Pro
85 90 95
Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala
100 105 110
<210> 8
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> VH domain
<400> 8
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Thr Tyr
20 25 30
Thr Met His Trp Val Lys Gln Arg Pro Arg Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Asn Ser Ala Ser Thr Ser Tyr Asn Glu Asn Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met His Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Tyr Thr Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
100 105 110
Thr Val Ser Ser
115
<210> 9
<211> 246
<212> PRT
<213> Artificial Sequence
<220>
<223> scFv derived from clone NA1/34.HLK
<400> 9
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Thr Tyr
20 25 30
Thr Met His Trp Val Lys Gln Arg Pro Arg Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Asn Ser Ala Ser Thr Ser Tyr Asn Glu Asn Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met His Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Tyr Thr Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Arg Asp Ile Gln Met Thr Gln Ser
130 135 140
Pro Ser Ser Leu Ser Ala Ser Leu Gly Gly Lys Val Thr Ile Thr Cys
145 150 155 160
Gln Ala Ser Gln Asp Ile Asn Lys Tyr Ile Ala Trp Tyr Gln Phe Lys
165 170 175
Pro Gly Lys Gly Pro Arg Leu Leu Ile His Tyr Thr Ser Thr Leu Gln
180 185 190
Pro Ala Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Arg Glu Tyr
195 200 205
Ser Phe Ser Ile Ser Asn Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr
210 215 220
Cys Leu His Tyr Asp Asn Leu Pro Trp Thr Phe Gly Gly Gly Thr Lys
225 230 235 240
Leu Glu Ile Lys Arg Ala
245
<210> 10
<211> 69
<212> PRT
<213> Artificial Sequence
<220>
<223> Transmembrane domain derived from CD8
<400> 10
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
1 5 10 15
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
20 25 30
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile
35 40 45
Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val
50 55 60
Ile Thr Leu Tyr Cys
65
<210> 11
<211> 113
<212> PRT
<213> Artificial Sequence
<220>
<223> Intracellular signaling domain derived from CD3ζ
<400> 11
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
50 55 60
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
65 70 75 80
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
85 90 95
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
100 105 110
Arg
<210> 12
<211> 42
<212> PRT
<213> Artificial Sequence
<220>
<223> Costimulatory signaling domain derived from CD137
<400> 12
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
1 5 10 15
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40
Claims (12)
1.一种用于治疗CD1a阳性癌症的方法中的T细胞,所述T细胞包含编码嵌合抗原受体(CAR)的核酸,所述嵌合抗原受体(CAR)包含:
(i)胞外结构域,所述胞外结构域包含CD1a靶向部分,其中所述CD1a靶向部分是包含由SEQ ID NO:7组成的VL结构域和由SEQ ID NO:8组成的VH结构域的scFV;
(ii)跨膜结构域;和
(iii)胞内信号传导结构域。
2.根据权利要求1所述用途的T细胞,其中,所述跨膜结构域包含CD28、CD3、CD45、CD4、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137或CD154的跨膜结构域。
3.根据权利要求2所述用途的T细胞,其中,所述跨膜结构域包含CD8的跨膜结构域。
4.根据权利要求1-3中任一项所述用途的化合物,其中,所述胞内信号传导结构域包含CD3ζ、FcRγ、CD3γ、CD3δ、CD3ε、CD5、CD22、CD79a、CD79b或CD66b的胞内结构域。
5.根据权利要求4所述用途的T细胞,其中,所述胞内信号传导结构域包含CD3ζ的胞内结构域。
6.根据权利要求1-5中任一项所述用途的T细胞,其中,所述CAR进一步包含共刺激信号传导结构域,优选地所述共刺激信号传导结构域包含CD27、CD28、CD137、CD134、CD30、CD40、淋巴细胞功能相关抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C、CD278或CD276的胞内结构域。
7.根据权利要求6所述用途的T细胞,其中,所述共刺激信号传导结构域包含CD137的胞内结构域。
8.一种用于治疗CD1a阳性癌症的方法中的药物组合物,所述药物组合物包含多个如前述权利要求中任一项所定义的细胞和药学上可接受的载体或稀释剂。
9.根据权利要求1-7中任一项所述用途的T细胞,其中,所述CD1a阳性癌症是皮质T细胞急性淋巴母细胞白血病,优选为复发性/难治性皮质T细胞急性淋巴母细胞白血病。
10.根据权利要求8所述的药物组合物,其中,所述CD1a阳性癌症是皮质T细胞急性淋巴母细胞白血病,优选为复发性/难治性皮质T细胞急性淋巴母细胞白血病。
11.根据权利要求1-7中任一项所述用途的T细胞,其中,所述CD1a阳性癌症是CD1a+T细胞淋巴母细胞性淋巴瘤,优选为复发性/难治性CD1a+T细胞淋巴母细胞性淋巴瘤。
12.根据权利要求8所述的药物组合物,其中,所述CD1a阳性癌症是CD1a+T细胞淋巴母细胞性淋巴瘤,优选为复发性/难治性CD1a+T细胞淋巴母细胞性淋巴瘤。
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EP19382104.8A EP3696191A1 (en) | 2019-02-14 | 2019-02-14 | Car t-cells for the treatment of cd1a-positive cancer |
PCT/EP2020/053769 WO2020165350A1 (en) | 2019-02-14 | 2020-02-13 | Car t-cells for the treatment of cd1a-positive cancer |
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EP (2) | EP3696191A1 (zh) |
JP (1) | JP2022520455A (zh) |
CN (1) | CN113795506A (zh) |
AU (1) | AU2020222239A1 (zh) |
CA (1) | CA3128955A1 (zh) |
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WO2022077021A1 (en) | 2020-10-09 | 2022-04-14 | Pfizer Inc. | CD1a ANTIBODIES AND USES THEREOF |
CA3220308A1 (en) * | 2021-05-26 | 2022-12-01 | Oxford University Innovation Limited | Antibodies |
IT202100027929A1 (it) * | 2021-11-02 | 2023-05-02 | Univ Degli Studi Magna Graecia Di Catanzaro | Un nuovo anticorpo bispecifico asimmetrico(UMG2/CD1a-CD3e) per il trattamento immunologico della forma corticale di leucemia linfoblastica acuta T (T-ALL) pediatrica e dell’adulto |
WO2023161530A1 (en) * | 2022-02-28 | 2023-08-31 | Onechain Immunotherapeutics S.L | HUMANIZED CD1a TARGETING MOIETY FOR THE TREATMENT OF CD1A-POSITIVE CANCER |
EP4234582A1 (en) * | 2022-02-28 | 2023-08-30 | Onechain Immunotherapeutics SL | Humanized cd1a targeting moiety for the treatment of cd1a-positive cancer |
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- 2020-02-13 CA CA3128955A patent/CA3128955A1/en active Pending
- 2020-02-13 US US17/430,705 patent/US20220143085A1/en active Pending
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US20220143085A1 (en) | 2022-05-12 |
EP3696191A1 (en) | 2020-08-19 |
EP3924374A1 (en) | 2021-12-22 |
AU2020222239A1 (en) | 2021-10-07 |
MX2021009798A (es) | 2021-11-17 |
WO2020165350A1 (en) | 2020-08-20 |
CA3128955A1 (en) | 2020-08-20 |
JP2022520455A (ja) | 2022-03-30 |
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